Recent Patents on Anti-Cancer Drug Discovery - Volume 10, Issue 2, 2015

Ovarian cancer accounts for more deaths than any other gynecologic malignancy. According to the Ovarian Cancer National Alliance, overall mortality rates due to ovarian cancer have not significantly improved in 40 years, a statistic that highlights the need for innovative treatment strategies. Immune checkpoint inhibitors are part of an emerging immunotherapeutic model that seeks to “inhibit the inhibitors” of adequate cancer immunosurveillance. Immune checkpoints encompass a variety of inhibitory pathways that downregulate an immune response, which allows them to assume an important physiologic role in maintaining homeostasis. While cancer cells are adept at utilizing these pathways to their advantage, basic scientists, translational researchers, and clinical trialists are making great strides in this area of investigation. This review article will focus on the development of anti-CTLA-4 and anti-PD1 monoclonal antibodies, their current role in the treatment of advanced stage EOC, and recently published patents that incorporate the use of immune checkpoint inhibition in the treatment of cancer.

Malignant growth of cells is a condition characterized by unchecked cellular proliferation, genetic instability and epigenetic dysregulation. Up-regulated HDAC (Histone Deacetylase) enzyme activity is associated with a closed chromatin assembly and subsequent gene repression, forming a characteristic feature of malignantly transformed cells. Novel therapeutics are now targeting the zinc containing HDAC enzymes for treating various types of cancers. Recently, a spate of drugs acting via HDAC inhibition have been undergoing clinical trials and several patents present exciting molecules like PCI-24781 (Abexinostat), ITF- 2357 (Givinostat); MS-275 (Entinostat), MGCD 0103 (Mocetinostat), LBH-589 (Panobinostat), FK228 (Romidepsin), PXD-101 (Belinostat) and Valproic Acid to be used as alternatives or adjuvants to traditional chemotherapeutics. However, only three HDAC inhibitors have acquired FDA approval till date. Recently, PXD-101 obtained FDA approval for the treatment of Refractory or Relapsed Peripheral T cell lymphoma. The current article reviews patents that have introduced novel molecules that are HDAC isoform specific, superior to first generation HDAC inhibitors like SAHA (Suberoylanilide Hydroxamic Acid) and TSA (Trichostatin A) and can be modified structurally to reduce toxic side effects and increase specificity. These molecules can combine the best characteristics of an ideal HDAC inhibiting drug either as monotherapy or in combinatorial therapy for cancer treatment thus, indicating promise to be included in the next generation of target specific HDAC inhibiting drugs.

The article reported an in-depth comparative technology analysis of 1708 Anti-cancer patents from top 20 international universities and leading 10 Indian public funded organization and research institutes. The study segregated pioneer universities vs. technologies used in the field of Anticancer research at a level of drug discovery, development, diagnosis and treatment, which are illustrated in the form of novel substantive patent landscape maps. The reported competitive intelligent maps identified genetics, composition and synthetic compounds as dominating technologies; followed by natural extracts, combination and drug delivery systems as upcoming technologies. The least number of patents were reported by surgical apparatus, targeted therapy and animal models. In addition, the study analysed the key technologies followed by Indian universities in comparison to the international universities, to identify the overlooked technologies by the Indian public funded institutes. In an ever changing competitive world, it is essential for every university to have their own research plan and thrust areas; but at the same time, it is equally important for any organisation to have an idea of their competitor’s research plan as well. So, the article suggested Indian institutes to focus on the latest emerging Anti-cancer technology trends, which are in practice by the international universities. Concurrently, this study may be a landmark indication for Indian public funded universities and institutes, calling for a U-turn from their traditional approaches.

Liver-related putative tumor suppressorlpts is a liver-related tumor suppressor candidate gene initially isolated by positional candidate cloning method. Three translation products of lpts gene are found, that are LPTS-L, LPTS-S and LPTS-M respectively. The gene highly expresses in normal tissues but lowly in cancer tissues. The LPTS proteins can suppress the activity of telomerase and trigger apoptosis for tumor cells in vivo and in vitro, despite that the detailed anti-cancer mechanism remains undefined. This review successively describes the lpts genomic assembly, transcriptional regulation and structure-activity evaluation of different LPTS isoforms; then it represents the LPTS binding partners, for example Pin2/TRF1 and MCRS2, which play important roles in decreasing telomerase activity, which benefits to reveal the anticancer mechanism; subsequently, it surveys several patents of recombinant LPTS proteins such as TAT-LPTS-LC, PinX1/C-G4S-9R-G4S-mBAFF and PinX1/C-9R-mBAF that can inhibit the growth of tumor cells. Lpts gene is becoming a promising drug target for cancer intervention owing to its powerful inhibition efficacy on telomerase activity, and recombinant LPTS proteins claimed by a couple of patents seem to be potential anti-cancer agents.

Specific elimination of tumor cells by replication-competent viral vectors is mediated through active viral replication, spread in tumor tissue and direct cytopathic effects. In addition, immune responses are induced against virally infected tumor cells. Recently, oncolytic vectors were constructed with mutations in neurovirulence genes or DNA synthesis genes. Viral replication should only be restricted to malignant cells to prevent severe viral disease. These constructed vectors terminate cells by mechanisms different from standard anti-cancer therapies; they offer another treatment modality which can be used in combination with chemotherapy, radiotherapy and gene therapies with additive or synergistic effects. Combination therapies are usually necessary to control tumorigenic diseases. Inhibiting angiogenesis represents another new field in current anticancer treatment development. Combining an oncolytic virus with antiangiogenesis is able to potentiate both treatment effects compared to each treatment modality alone in both primary and advanced disease. This combination might be beneficial for cancer patients in the future. We have also outlined some relevant patents.

Lung cancer is the leading cause of malignancy-related mortality worldwide. Metastases, which account for 90% of lung cancer deaths, frequently target the skeleton, leading to rapid deterioration in quality of life and premature death. The molecular mechanism underlying this progression, especially the development of bone metastases, is largely unknown. MicroRNAs (miRNAs) are small, endogenous, noncoding RNAs that function as negatively posttranscriptional gene regulators. Changes in miRNAs, which may exhibit either oncogenic or tumor suppressive activity, are common in lung cancer. Over-expressed miRNAs may contribute to oncogenesis by down-regulating tumor suppressors, whereas the loss of selected miRNAs may negatively regulate oncogenes or factors related to tumorigenesis and progression. MiRNAs may activate or repress metastases. Specific miRNA expression profiles may correlate with the response in treatment. We summarize recent findings and patents in the pathological roles of miRNAs in the progression and bone metastases in lung cancer, and discuss the diagnostic and therapeutic options in the clinical management of lung cancer.

The degradation of intracellular proteins is targeted by ubiquitin via non-lysosomal proteolytic pathway in the cell system. These ubiquitin molecules have been found to be conserved from yeast to humans. Ubiquitin proteasome machinery utilises ATP and other mechanisms for degrading proteins of cytosol as well as nucleus. This process of ubiquitination is regulated by activating the E3 enzyme ligase, involved in phosphorylation. In humans, proteins which regulate the cell cycle are controlled by ubiquitin; therefore the ubiquitin-proteasome pathway can be targeted for novel anti-cancer strategies. Dysregulation of the components of the ubiquitin system has been linked to many diseases like cancer and inflammation. The primary triggering mechanism (apoptosis) of these diseases can also be induced when TNF-related apoptosis-inducing ligand (TRAIL) binds to its specific receptor DR4 and DR5. In this review, the emerging prospects and importance of ubiquitin proteasome pathway as an evolving anticancer strategy have been discussed. Current challenges in the field of drug discovery have also been discussed on the basis of recent patents on cancer diagnosis and therapeutics.

Different studies have shown the role of neurotransmitters (e.g., dopamine) in the progression of cancers via their various types of receptors. The aim of this study was to determine the pattern of dopamine receptors gene expression on MCF-7 cells and to evaluate the selective dopamine receptors agonist and antagonist effects on them. In addition, some other discoveries which are patented for the treatment of breast cancer are reviewed in this article. To determine the pattern of dopamine receptors gene expression in human breast cancer cells (MCF-7), RT-PCR was performed. Then, MCF-7 cells were treated by different doses of bromocriptine and remoxipride for 48 hours. Cell viability was evaluated by MTT assay. Thus, nuclear morphology of cells was analyzed by mixed dye florescent staining. Real time PCR technique was performed to determine the decreasing rate of proliferating cell nuclear antigen (PCNA) gene expression in treated MCF-7 cells. Finally, quantification of apoptosis and its difference with necrosis at the single cell level were assessed by Flowcytometery technique. This study revealed that, unlike remoxipride, bromocriptine suppressed proliferation of the MCF-7 cells (54.3% at 12.5 μM bromocriptine concentration), but remoxipride could suppress the effect of bromocriptine. Bromocriptine has inhibitory effects on MCF- 7 cells by induction of apoptosis via D2-like receptors. Therefore, in future studies, bromocriptine can be used as a new choice for the treatment of tumoral breast cancer cells.

Many anticancer drugs that are currently used in cancer treatment are natural products or their analogues by structural modification. Caffeic acid (3, 4-dihydroxycinnamic acid; CA) is classified as hydroxycinnamic acid and has a variety of potential pharmacological effects, including antioxidant, immunomodulatory and anti-inflammatory activities. As a drug carrier, solid lipid nanoparticles (SLNs) introduced to improve stability, provide controlled drug release, avoid organic solvents and are obtained in small sizes. In this study, we developed solid lipid nanoparticles incorporating with caffeic acid using hot homogenization method. Caffeic acid loaded solid lipid nanoparticles were characterized regarding particle size, zeta potential, drug entrapment efficiency, drug release, scanning electron microscopy (SEM) and FT-IR. The effects of caffeic acid loaded solid lipid nanoparticles on MCF-7 cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dimethyl tetrazolium bromide (MTT) test and Annexin V-PI analysis. As a result, solid lipid nanoparticles could potentially be used for the delivery of caffeic acid and solid lipid nanoparticles formulation enhanced the effects of caffeic acid on MCF-7 cells. Some relevant patents are also referred in this article.

Background: The forte of research today aims at determining genotoxic changes in human cells as rapidly as possible. Micronuclei estimation in exfoliated cells is an easy, noninvasive and a reliable method to monitor genotoxic changes due to various reasons in oral mucosal cells. Aims and Objectives: To identify, quantify and compare micronuclei in exfoliated buccal mucosal cells of healthy, oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC) participants. Patients and Methods: In the present study, buccal smears from the 60 participants (30 each of OSMF and OSCC) and 30 age and sex matched controls were obtained and stained using Papanicolaou (PAP) staining method and observed under 100X magnification to identify and quantify micronuclei in the exfoliated cells of oral mucosa. Results: There was a significant increase in micronuclei count from control to OSMF to OSCC. Also, a significant increase in the micronuclei frequency is observed with the different clinical stages and histological grades of OSMF and different histological grades of OSCC. Conclusion: Micronucleus assay can be used as an easy and consistent marker for genotoxic evaluation in higher risk groups and can be used for better treatment evaluation and prognosis in cases of OSMF and OSCC. Some relevant patents are also outlined in this article.